Beyond Proteolysis-Targeting Chimeric Molecules: Designing Heterobifunctional Molecules Based on Functional Effectors

Abstract

In recent years, with the successful development of proteolysis-targeting chimeric molecules (PROTACs), the potential of heterobifunctional molecules to contribute to reenvisioning drug design, especially small-molecule drugs, has been increasingly recognized. Inspired by PROTACs, diverse heterobifunctional molecules have been reported to simultaneously bind two or more molecules and bring them into proximity to interaction, such as ribonuclease-recruiting, autophagy-recruiting, lysosome-recruiting, kinase-recruiting, phosphatase-recruiting, glycosyltransferase-recruiting, and acetyltransferase-recruiting chimeras. On the basis of the heterobifunctional principle, more opportunities for advancing drug design by linking potential effectors to a protein of interest (POI) have emerged. Herein, we introduce heterobifunctional molecules other than PROTACs, summarize the limitations of existing molecules, list the main challenges, and propose perspectives for future research directions, providing insight into alternative design strategies based on substrate-proximity-based targeting.

PROTACs bearing piperazine-containing linkers: what effect on their protonation state?

“…Noteworthy, in this study we intentionally focus on PROTAC molecules and their precursors but many observations related to the effect of piperazine-containing linkers can be beneficial also for the design and optimization of other kind of heterobifunctional compounds e.g. , lysosome-targeting chimera LYTAC, autophagy-targeting chimera AUTAC, RIBOTAC, 13 molecular glues, 14,48 and antibody–drug conjugates, 9–12 among others.…”

“…Both the length and composition of the linker are critically important for the formation of a productive ternary complex, degradation activity, and target selectivity. 7 Moreover, as commonly observed also in other chimeric compounds 8 (including antibody–drug conjugates (ADC), 9–12 dual-inhibitors, and molecular glues 13,14 ), the linker has a significant impact on the overall physicochemical properties of the PROTAC molecule, which in turn affect its pharmacokinetic (PK) profile. 15 Several advantages of PROTAC technology over traditional protein inhibition were highlighted, including the catalytic mechanism (once degradation occurs, the PROTAC molecule can bind to a new target molecule) and the ability to bind targets considered “undruggable” with classical small molecule inhibitors, just to mention a few.…”

A New In-Silico Approach for PROTAC Design and Quantitative Rationalization of PROTAC mediated Ternary Complex Formation

“…Also, in future work we see the scope of generalizing the workflow for other heterobifunctional therapeutics such as DUBTAC, LYTAC, AUTAC, PhosTAG (Hua et al (2022) [11]) and others where a hetero-bifunctional molecule mediated ternary complex formation is involved.…”

“…We believe that the computational ability to calculate PROTAC performance metrics measured in PROTAC experimental assays would bring significant time reduction and cost cutting advantages to the DMTA cycle of PROTAC design. Also, in future work we see the scope of generalizing the workflow for other hetero-bifunctional therapeutics such as DUBTAC, LYTAC, AUTAC, PhosTAG (Hua et al (2022) [11]) and others where a hetero-bifunctional molecule mediated ternary complex formation is involved.…”

Targeted protein posttranslational modifications by chemically induced proximity for cancer therapy

“…By taking advantage of proximity chemistry, the aforementioned heterobifunctional molecules are designed to introduce or remove native or neo-PTM on protein targets, thereby activating or deactivating the POIs ( 108 , 109 ). In addition, a recent preprint article has demonstrated the potential of a bifunctional molecule platform called regulated induced proximity targeting chimera (RIPTAC), which could elicit a designed PPI.…”